Pairs Of Molecules Research Articles

Can We Quickly Learn to "Translate" Bioactive Molecules with Transformer Models?

Meaningful exploration of the chemical space of druglike molecules in drug design is a highly challenging task due to a combinatorial explosion of possible modifications of molecules. In this work, we address this problem with transformer models, a type of machine learning (ML) model originally developed for machine translation. By training transformer models on pairs of similar bioactive molecules from the public ChEMBL data set, we enable them to learn medicinal-chemistry-meaningful, context-dependent transformations of molecules, including those absent from the training set. By retrospective analysis on the performance of transformer models on ChEMBL subsets of ligands binding to COX2, DRD2, or HERG protein targets, we demonstrate that the models can generate structures identical or highly similar to most active ligands, despite the models having not seen any ligands active against the corresponding protein target during training. Our work demonstrates that human experts working on hit expansion in drug design can easily and quickly employ transformer models, originally developed to translate texts from one natural language to another, to "translate" from known molecules active against a given protein target to novel molecules active against the same target.

Crystal structure and Hirshfeld surface analysis of (22 RS,23 SR,25 RS,26 SR)-23,25,5-trimethyl-21-(2,2,2-tri-fluoro-acet-yl)-5-aza-2(2,6)-piperidina-1,3(2,5)-di-furana-cyclo-hexa-phan-24-one.

The title compound, C20H21F3N2O4, features a main twelve-membered difuryl ring with which the furan rings make dihedral angles of 76.14 (5) and 33.81 (5)°. The dihedral angle between the furan rings is 42.55 (7)°. The six-membered nitro-gen heterocycle has a twist-boat conformation. In the crystal, pairs of mol-ecules are connected by inter-molecular C-H⋯O inter-actions, generating an R 2 2(14) ring motif. These pairs of mol-ecules form zigzag chains along the a-axis direction by means of C-H⋯F inter-actions. Furthermore, C-H⋯π and C-F⋯π inter-actions link the mol-ecules into chains along the b-axis direction, forming sheets parallel to the (001) plane. These sheets are also connected by van der Waals inter-actions.

Exploring isofunctional molecules: Design of a benchmark and evaluation of prediction performance.

Identification of novel chemotypes with biological activity similar to a known active molecule is an important challenge in drug discovery called 'scaffold hopping'. Small-, medium-, and large-step scaffold hopping efforts may lead to increasing degrees of chemical structure novelty with respect to the parent compound. In the present paper, we focus on the problem of large-step scaffold hopping. We assembled a high quality and well characterized dataset of scaffold hopping examples comprising pairs of active molecules and including a variety of protein targets. This dataset was used to build a benchmark corresponding to the setting of real-life applications: one active molecule is known, and the second active is searched among a set of decoys chosen in a way to avoid statistical bias. This allowed us to evaluate the performance of computational methods for solving large-step scaffold hopping problems. In particular, we assessed how difficult these problems are, particularly for classical 2D and 3D ligand-based methods. We also showed that a machine-learning chemogenomic algorithm outperforms classical methods and we provided some useful hints for future improvements.

Electro‐Optical Properties of MBBA Liquid Crystal Surrounded by Acetonitrile Medium Enhanced under the Presence of Electric Field: An Ab Initio Study

AbstractThis study has used ab initio technique to investigate the electro‐optical and electronic properties of N‐(4‐methoxybenzylidene)‐4‐butylaniline (MBBA), a nematic liquid crystal between 21 and 48 °C, surrounded by gas and acetonitrile medium, in the presence and absence of electric field. The optimization and analysis of various electro‐optical and electronic parameters along with absorption spectrum have been performed using ωB97xD/6‐311+G(d,p) and M062X/6‐311+G(d,p) methods. Under the electric field, electro‐optical parameters of MBBA surrounded by acetonitrile are increased, indicating its suitability for display device development application. Global reactivity descriptors reveal that electronic properties of the MBBA LC also high in acetonitrile medium as compared to that of the gas. Furthermore, using second order perturbation theory and the multicentered‐multipole expansion technique, the mutual interactions between a pair of MBBA molecules are examined, revealing the nematic behavior of MBBA molecule.

Design, synthesis, and stability of (1-amino-4-(3-bromopropoxy)anthracene-9,10‑dione)pentacarbonylrhenium(I) triflate: first X-ray crystallographic structure of a Re(CO)5(N-donor)

In a bid to functionalise doxorubicin with rhenium carbonyl, we designed and synthesized two doxorubicin analogues, 1-(3-trimethylammoniumpropoxy)-4-hydroxyanthraquinone triflate (A1) and 1-amino-4-(3-trimethylammoniumpropoxy) anthraquinone triflate (A2), via a simple 3-step procedure, and obtained X-ray crystal structures for them. Reaction of A1 with Re(CO)5(OTf) afforded complex 1 in 40% yield. Based on a combination of ultraviolet/visible, proton nuclear magnetic resonance spectroscopies, density functional theory calculations, and, in particular, infrared spectroscopy and electrospray ionization mass spectrometry, complex 1 was deduced to be [{fac-Re(CO)3(κ2-deproto-A1)}2(μ2OTf)]OTf, in which A1 coordinates to Re in a bidentate fashion and a triflate anion bridges two Re(CO)3 moieties. Reaction of A2 with various rhenium carbonyl synthons was intractable, but 1-amino-4-(3-bromopropoxy)anthraquinone (A2-a), a precursor of A2, reacted with Re(CO)5(OTf) to yield complex 2 in 65% yield. A single crystal X-ray crystallographic study established complex 2 to be [Re(CO)5(A2-a)]OTf, in which the -NH2 of A2-a coordinates to Re in a monodentate fashion. Complex 2 crystallized in the P21/n monoclinic space group and packs by vertically stacking on top of each other and with a horizontal displacement of 49° from the neighbouring pairs of molecules. This is similar to the crystal packing of A1, but not A2. We observed that complexes 1 and 2 are unstable in solution, and dissociated in dimethylsulfoxide with first order rate constants of 0.029 ± 0.001 h−1 and 18 ± 2 h−1 respectively; in water, complex 1 dissociated almost immediately. Molecular orbital analysis indicated that the low bonding interaction between the coordinating atoms and Re for complex 1 and high energy of the bonding molecular orbital for complex 2 are likely to be the basis of weak coordination of the anthraquinones to rhenium carbonyl. Thus, with regard to the intended objective to modulate the pharmacological profile of doxorubicin, direct coordination of rhenium carbonyl is certainly not feasible.

Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance.

Circulating tumor cells (CTCs), shed by primary malignancies, function as "seeds" for distant metastasis. However, it is still largely unknown how CTCs escape immune surveillance. Here, we characterize the transcriptomes of human pancreatic ductal adenocarcinoma CTCs, primary, and metastatic lesions at single-cell scale. Cell-interaction analysis and functional studies invitro and invivo reveal that CTCs and natural killer (NK) cells interact via the immune checkpoint molecule pair HLA-E:CD94-NKG2A. Disruption of this interaction by blockade of NKG2A or knockdown of HLA-E expression enhances NK-mediated tumor cell killing invitro and prevents tumor metastasis invivo. Mechanistic studies indicate that platelet-derived RGS18 promotes the expression of HLA-E through AKT-GSK3β-CREB signaling, and overexpression of RGS18 facilitates pancreatic tumor hepatic metastasis. In conclusion, platelet-derived RGS18 protects CTCs from NK-mediated immune surveillance by engaging the immune checkpoint HLA-E:CD94-NKG2A. Interruption of the suppressive signaling prevents tumor metastasis invivo by immune elimination of CTCs.

(Z)-4,5-Di-bromo-3,3,6,6-tetra-methyl-2,3,6,7-tetra-hydro-thiepine-1,1-dione.

The crystal of the title compound, C10H16Br2O2S, is formed from layers built from centrosymmetric pairs of mol-ecules. The mol-ecule adopts a twist conformation with the carbon atoms next to sulfur above or below the mean plane.

Packing structure and non-classical hydrogen bonding interactions of the toluene solvate crystal of 1,8-bis(4-methylbenzoyl)naphthalene-2,7-diyl dibenzoate: Role of toluene molecule in determination of the spatial arrangement of the major constituent molecules

The toluene solvate crystal of the titled highly congested aromatic ketone-ester compound has been subjected to crystal structural analysis from the viewpoints of the clarification of distribution feature of effective non-classical hydrogen bonds and the retention and perturbation of the symmetric nature. The two independent molecules of the title naphthalene derivative, which bears two aroyl groups at the adjacent inner positions and two benzoyloxy groups at the neighboring β-positions, and one disordered solvent toluene molecule are incorporated in the asymmetric unit of P21 /c (Z′= 2). In the packing of the solvate crystal, the solvent toluene molecule plays the multi roles of hydrogen donor/acceptor for C–H…π non-classical hydrogen bonds and hydrogen donor for C–H…O = C ones. On the other hand, the role of other benzene rings of the parts of the title compound molecules is confined. The 4-methylbenzoyl groups situated at the molecular inner positions mainly play the role of the hydrogen donor of C–H…π non-classical hydrogen bond. The benzoyloxy groups that extend outward from the molecular body mainly act as the hydrogen acceptors of C–H…O and C–H…π non-classical hydrogen bonds. The naphthalene ring moderately contributes as the hydrogen acceptor for C–H…π non-classical hydrogen bonds and as the hydrogen donor for C–H…O non-classical hydrogen bonds. The roles of the toluene molecule are not limited to a simple filler for the void among the major constituent molecules but proved to position at the pseudo-centrosymmetric center of the counter-configurated pair of molecules of the independent major component compounds to concentrate the effective non-classical hydrogen bonds.

Comprehensive evaluation of zwitterionic hydrophilic liquid chromatography stationary phases for oligonucleotide characterization

Hydrophilic interaction chromatography (HILIC) has been proposed as a valuable alternative to ion-pairing reversed-phase chromatography (IP-RPLC) for oligonucleotide (ON) analysis. In this context, the potential of seven zwitterionic HILIC columns has been evaluated against amide- and poly-hydroxy fructan-functionalized HILIC columns and a C18 column operated under IP-RPLC mode.Based on the retention characteristics of key small molecule pairs, each zwitterionic HILIC column showed a unique radar-shaped profile, suggesting different selectivities for distinct structural differences. Unmodified DNA and RNA samples were then evaluated, and the columns classified based on their retentivity. Two zwitterionic columns were particularly promising in terms of overall resolution, especially for the largest ONs (> 40-mer). Finally, separations between a chemically modified drug-like ON and its closely related impurities were performed. Although the ZIC-cHILIC column showed similar selectivity values as compared to the reference IP-RPLC technique, all columns demonstrated a general decrease in selectivity due to the minor structural differences present in the highly complex samples.This work highlights the utility of zwitterionic HILIC mode for ON analysis and it reveals the importance of understanding columns characteristics – in terms of retention and selectivity – when selecting a stationary phase for specific ON applications.

Long‐Lived Charge Separation Induced Organic Long‐Persistent Luminescence with Circularly Polarized Characteristic

AbstractResearch on strategies to enable organic long‐persistent luminescence (LPL) emission with circularly polarized luminescence (CPL) characteristics is still very rare due to the lack of an unambiguous light‐emitting mechanism. Herein, circularly polarized long‐persistent luminescence (CPLPL) of a pair of axial chiral molecules as the guest is induced under ambient conditions by exploiting the long‐lived charge separation of the host–guest doping system, whose LPL performance can be further promoted by introducing a rigid polymer network to enhance the charge separation efficiency between host and guest. Based on these CPLPL materials, an effective combination of CPL and LPL properties that is “difficult to copy” is revealed for information encryption and anticounterfeiting applications. This work is expected to stimulate a research boom of CPLPL materials, and will hopefully promote the development of organic LPL systems.

The Basic Nature of Intermolecular Attraction Forces Newtonian Gravitation Shown by Deriving ‘Diffusion’

Here in this paper, we show that the basic reason for this diffusion is the intermolecular attraction forces due to Newtonian gravitational attraction forces acting in a combined way which are the vectorial sum of all the attraction forces acting on molecules as defined as SITA forces Multi Molecule Theory. Some pairs of molecules hit each other and bounce like rubber balls and diffuse because of these SITA forces. Here some of the molecules are going to higher distances from the hitting centers. Earlier we formulated and showed the three states of matter in a similar way. Here we took a Nano-drop-let of contaminated water as a container. We are calculating intermolecular attraction forces between molecules and finding the movements of molecules as a result of the attraction by all the other molecules at the molecular level.

The self-assembly of a pair of low-symmetry tetracarboxylic acid molecules and their co-assembly with bridging molecules at the liquid-solid interface.

The supramolecular self-assembly behavior of a pair of low-symmetry tetracarboxylic acid molecules (H4OBDB and H4ADDI) and their co-assembly behavior with TMA as a bridging molecule were studied at the liquid-solid interface. Scanning tunneling microscope (STM) observations revealed that H4OBDB and H4ADDI molecules both tend to form O-shaped dimers but end up forming different types of self-assembly structures. We also investigated the construction of two-component co-assembly structures by mixing H4OBDB or H4ADDI molecules with bridging molecules such as TMA. The two formed co-assembly structures are similar. Based on the analysis of the STM results and the density functional theory (DFT) calculations, the formation mechanism of the assembled structures was revealed.

A machine learning framework to predict the aggregation of polycyclic aromatic compounds

The physical aggregation of polycyclic aromatic compounds (PACs) is a key step in soot inception. In this work, we set out to elucidate which molecular properties of PACs influence the physical growth process and develop a machine learning framework to quantitatively relate these features to the propensity of PACs to physically dimerize. To this end, we identify a pool of compounds with a diverse range of properties and create a dataset of PAC monomers along with their calculated free energies of dimerization, obtained via molecular dynamics simulations enhanced by well-tempered Metadynamics. We then demonstrate that a machine learning model based on the least absolute shrinkage and selection operator (Lasso) is able to quantitatively learn how molecular features contribute to physical aggregation and predict the free energy of dimerization for new pairs of molecules. Results show that our model is able to accurately determine the stability of dimers obtained from both homo- and hetero-molecular dimerization cases. Our approach provides also a data driven method to determine the molecular features most important to predicting the dimer stability. Indeed, we identified size, shape, oxygenation, and presence of rotatable bonds as the most influential characteristics of PACs that contribute to physical dimerization. This work highlights the molecular complexity of the PAC monomers that must be accounted for in order to accurately represent physical aggregation. We anticipate that our approach is key to modeling soot inception as it allows for the efficient prediction of dimerization propensity from easily calculable molecular features.

The sliding motility of the bacilliform virions of Influenza A viruses.

Influenza A virus (IAV) infection relies on the action of the hemagglutinin (HA) and neuraminidase (NA) membrane proteins. The HA ligands anchor the IAV virion to the cell's surface by binding the sialic acid (SA) present on the host's receptors while NA is an enzyme capable of cleaving the SA from the extracellular environment. It is believed that the activity of NA ligands increases the motility of the virions favoring the propagation of the infection. In this work, we develop a numerical framework to study the dynamics of a virion moving across the cell surface for timescales much bigger than the typical ligand-receptor reaction times. We find that the rates controlling the ligand-receptor reactions and the maximal distance at which a pair of ligand-receptor molecules can interact greatly affect the motility of the virions. We also report on how different ways of organizing the two types of ligands on the virions' surface result in different types of motion that we rationalize using general principles. In particular, we show how the emerging motility of the virion is less sensitive to the rate controlling the enzymatic activity when NA ligands are clustered.

Optical sensor array of chiral MOF-based Fabry-Pérot films for enantioselective odor sensing.

An optical sensor array based on photonic Fabry-Pérot films of surface-mounted metal-organic-frameworks (SURMOFs) with different homochiral structures is presented. It is used to detect and enantioselectively discriminant 3 pairs of chiral odor molecules, either pure or in binary mixtures.

Complementary host behaviour of three anthracenyl-derived roof-shaped compounds in mixed pyridines

Three roof-shaped host compounds possessed complementary selectivity behaviour in mixed pyridines. This stereoview shows the inclusion of a pair of guest molecules by six host molecules in H3·2MePy. (Guest carbon atoms are in black for contrast).

Recent advances in material chemistry for zinc enabled redox flow batteries

AbstractThe pursuit of green and sustainable energy is a long‐term goal for modern society and people's life. Particularly under the context of carbon neutralization, decarbonization has become a consensus and propels the turning of research enthusiasm to explore new materials and chemistries for energy conversion and storage at a low expenditure. Zinc (Zn) enabled redox flow batteries (RFBs) are competitive candidates to fulfill the requirements of large‐scale energy storage at the power generation side and customer end. Considering the explosive growth, this review summarizes recent advances in material chemistry for zinc‐based RFBs, covering the cathodic redox pairs of metal ions, chalcogens, halogens, and organic molecules. After a brief introduction of common issues for Zn2+/Zn conversion reaction at the anode side, the focus is devoted to expounding challenges of redox species and possible problem‐solving strategies at the cathode side. Besides, the auxiliary components of separator and current collector are also discussed for achieving optimal RFBs' performance. At last, the conclusion and outlook of future endeavor for Zn‐based RFBs implementation are put forward.

New polymorphic phase of arachidic acid crystal: structure, intermolecular interactions, low-temperature stability and Raman spectroscopy combined with DFT calculations.

Saturated monocarboxylic fatty acids with long carbon chains are organic compounds widely used in several applied fields, such as energy production, thermal energy storage, antibactericidal, antimicrobial, among others. In this research, a new polymorphic phase of arachidic acid (AA) crystal was synthesized and its structural and vibrational properties were studied by single-crystal X-ray diffraction (XRD) and polarized Raman scattering. The new structure of AA was solved at two different temperature conditions (100 and 300 K). XRD analysis indicated that this polymorph belongs to the monoclinic space group P21/c (C2h5), with four molecules per unit cell (Z = 4). All molecules in the crystal lattice adopt a gauche configuration, exhibiting a R22(8) hydrogen bond pattern. Consequently, this new polymorphic phase, labeled as B form, is a polytype belonging to the monoclinic symmetry, i.e., Bm form. Complementarily, Hirshfeld's surfaces were employed to analyze the intermolecular interactions within the crystal lattice of this polymorph at temperatures of 100 and 300 K. Additionally, density functional theory (DFT) calculations were performed to assign all intramolecular vibration modes related to experimental Raman-active bands, which were properly calculated using a dimer model, considering a pair of AA molecules in the gauche configuration, according to the solved-crystal structure.

Cross Second Virial Coefficients of the H2O–H2S and H2O–SO2 Systems from First Principles

The cross second virial coefficients B12 for the interactions of water (H2O) with hydrogen sulfide (H2S) and of water with sulfur dioxide (SO2) were determined at temperatures from 200 to 2000 K employing new intermolecular potential energy surfaces (PESs) for the H2O–H2S and H2O–SO2 molecule pairs. The PESs were fitted to interaction energies calculated for more than 50 000 configurations of each molecule pair using quantum-chemical ab initio methods up to coupled cluster with single, double, and perturbative triple excitations [CCSD(T)] with consideration of relativistic effects. The B12 values were extracted from the PESs both classically and semiclassically using the Mayer-sampling Monte Carlo scheme. In addition, accurate correlations of the final B12 values were used to derive the dilute gas cross isothermal Joule–Thomson coefficients, ϕ12 = B12 – T(dB12/dT). For both investigated systems, Wormald provided the only experimentally based B12 and ϕ12 values available in the literature. While his B12 values, which he obtained from the ϕ12 data with the aid of model potentials, are not in satisfying agreement with the present B12 values, his ϕ12 data, after a reanalysis using more accurate pure-component ϕ values, agree very well with the calculated ϕ12 values of this work.

Binaphthanol-derived emitters with aggregation-induced emission, acidochromic and chiral optical properties

The development of chiral organic fluorescent molecules has attracted broad attention for their various optical applications. In this work, four pairs of chiral fluorescent molecules based on binaphthanol structure have been designed and synthesized. These molecules show blue fluorescent emission in organic solvents with good fluorescent quantum yields and large Stokes shifts. The molecules with benzoxazole moiety display aggregation-induced emission effect in methanol/water solutions, while molecules with quinazolinone moiety show aggregation-caused quenching properties. Moreover, compounds with quinazolinone moiety exhibit acidochromic properties in aqueous solution with different pH values, and their emission intensity are significantly enhanced in strongly acidic conditions. The chiral molecules generally have good circular dichroism intensity. Their R- and S- enantiomers show mirror-imaged circular dichroism curves. Further studies reveal that compound with mono quinazolinone moiety has specific aggregation-induced circular dichroism enhancement properties. This work provides a new strategy for obtaining chiral BINOL-based fluorescent molecules with unique optical properties.